Autonomic dysfunction is an increasingly recognized problem in aging humans. We have demonstrated that aging in both the human and rodent sympathetic nervous system is characterized by the reproducible development of distinctive, markedly enlarged, terminal axons and synapses with the histopathologic appearance of neuroaxonal dystrophy (NAD). We have made several recent discoveries which represent significant advances in understanding the pathogenesis of age-related autonomic dysfunction and now propose a focused analysis of synapse- associated events that may underlie human disease. We have found that short courses of IGF-I or NT-3 result in significant reduction in established sympathetic NAD in aged rats. Contrary to conventional thinking, age-related sympathetic NAD is not a simple NGF deficiency disease and, surprisingly, exogenously administered NGF may actually worsen NAD. Since our last submission, we have discovered that suicidal ingestion of paraquat (PQ), a superoxide-generating herbicide, results in autonomic failure and the development of NAD in human sympathetic ganglia, identical in structure and immunoprofile to that found in aging. We have found that PQ also produces dystrophic axons in cultures of rat sympathetic neurons, which promises to provide mechanistic insights into the proposed oxidative pathogenesis of age-related sympathetic NAD. Based on our studies, we propose that NAD is a distinctive neuropathological end-point whose formation critically interferes with synaptic transmission and results from a combination of oxidative nerve terminal injury and defective synaptic adaptation. We propose in the current research plan to test the following hypotheses: 1) that oxidative stress causes nerve terminal injury and is the initiating stimulus in the development of age-related NAD; 2) that NAD reflects an age-related defect in synaptic plasticity, collateral axonal sprouting and/or regeneration; 3) that this defect is, at least in part, secondary to an age-related excess of NGF and diminished IGF-1 and NT-3; and, 4) that NAD formation leads to defective interneuronal signal transmission and endorgan dysfunction. The results of these experiments should provide insight not only into autonomic dysfunction, but into a variety of pathologic processes in which NAD is a prominent component.